The long-term goal of this research is to identify and validate the proteomic changes in the development of neurodegeneration. Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative diseases. Although AD and PD are considered distinct disorders, significant overlap occurs. Mild cognitive impairment (MCI) is a transient state between healthy aging and dementia, often representing a very early stage of cognitive decline associated with a degenerative dementing illness. Histopathologically, accumulation of abnormal proteins has been recognized as hallmarks of neurodegeneration in both AD and PD, suggesting that shared molecular mechanisms may mediate the pathogenesis of neurodegeneration in AD, PD, and AD/PD overlap disorders. Using novel mass spectrometry-based technologies, we will test our central hypothesis: changes in the ubiquitinated proteome and the postsynaptic proteome will reveal molecular commonality among AD, PD, and AD/PD overlap syndromes, and changes in protein patterns will accompany the evolution of disease from MCI to AD. We will use clinically well-characterized human postmortem samples to evaluate protein pattern changes in the ubiquitinated proteome and in the postsynaptic density (PSD). Samples of MCI, AD, PD and AD/PD overlap disease will be analyzed and compared to discover shared protein patterns. These protein changes will be further confirmed in a large set of disease cases. The results will enable the identification of potential biomarkers and provide critical molecular maps for subsequent studies of neurodegeneration.